Acquired Immunodeficiency Syndrome (AIDS) was coined in 1982 to describe the clinical manifestations of immunodeficiency. The etiological agent of AIDS was later associated with a retrovirus, Human Immunodeficiency Virus (HIV), from the lentivirus subfamily. At least two infectious strains of HIV have been identified, HIV-1 and HIV-2. Here, HIV will be used as a general term describing all strains and mutants of the Human Immunodeficiency Virus. The detailed study of HIV has given rise to many approaches to antiviral drug development including inhibition of the viral aspartyl protease (D. Richman, Control of Virus Diseases, 45th Symposium of the Society for General Microbiology, 261-313 (1990)).
Aspartyl proteases have been found in many retroviruses including the Feline Immunodeficiency Virus (FIV), the Myeloblastosis Associated Virus (MAV), HIV, and the Rous Sarcoma Virus (RSV) H. Toh et al. Nature, 315: 691 (1985); J. Kay, B. M. Dunn, Biochim. Biophys. Acta, 1: 1048 (1990); C. Cameron, J. Biological Chem., 168: 11711-720 (1993)!. Since there are structural similarities among the known retroviral proteases, compounds which inhibit the HIV protease may well inhibit other retroviral proteases.
HIV aspartyl protease is responsible for post-translational processing of viral precursor polyproteins such as pol and gag. (M. Graves, Structure and Function of the Aspartic Proteases, 395-405 (1991)). Cleavage of these polyproteins by this protease is essential for maturation of the virus, since the proteolytic activity necessary for polyprotein processing cannot be provided by host cellular enzymes. An important finding has been that viruses which lack this protease, or contain mutations which produce defective proteases, lack infectivity C. Peng et al., J. Virol., 63: 2550-2556 (1989) and K. Kohl et al., Proc. Nati. Acad. Sci. USA, 85: 4686-9 (1987)!. Thus, a selective HIV protease inhibitor has been shown to inhibit viral spread and the production of cytopathic effects in cultures of acutely infected cells (J. C. Craig, et al., Antiviral Research, 16: 295-305 (1991)). For this reason, inhibition of HIV protease is believed to be a viable approach to antiviral therapy.
HIV protease inhibitors have been extensively reviewed (see for example A. Tomasselli et al., Chimica Oggi, 9: 6-27 (1991) and T. Meek, J. Enzyme Inhibition, 6: 65-98 (1992)). However, the majority of these inhibitors are peptides and thus unsuitable as drugs, due to the well known pharmacological deficiencies exhibited by most peptide drugs (biliary excretion, low-bioavailability and stability in physiological milieu, etc.) Nonpeptidic inhibitors of HIV protease are thus very important, since these may lead to very useful therapeutic agents.
Coumarins containing a 4-methyl or -phenyl substituent were claimed as anticancer agents in JP 92075911-B, and 4-hydroxy coumarins (shown below), with sulfur-containing alkyl and substituted phenyl substituents at the 3-position, were active as plant growth stunting and antimicrobial agents, according to U.S. Pat. No. 3,810,922. ##STR1##
World Patents 92/04326, WO 92/04327, WO 92/04328, and U.S. Pat. No. 5,179,107 claim quinolinones and certain coumarins with activity against DNA viruses, such as Herpes Simplex Virus (HSV), Epstein-Barr Virus (EBV), and Cytomegalovirus (CMV).
World Patent 91/04663 reports the use of 6-amino-1,2-benzopyrone derivatives in the treatment of diseases caused by viruses, such as HIV, HSV and CMV, but only one compound was actually tested. The postulated mechanism of action involves oxidation of the amine to the 6-nitroso derivative which proceeds to oxidize a thiol side chain in the zinc finger of adenosine diphosphoribose transferase (ADPRT) causing ejection of complexed zinc. Thus the 6-amino group was the essential feature of those agents.
World Patent 92/06687 claims the use of 5-iodo-6-amino-1,2-benzopyrones as cytostatic and antiviral agents in mammalian hosts with activity against herpes and HIV viruses. The mechanism of action of these compounds may be related to ADPRT processing. Nevertheless, no satisfactory mechanism of action was proposed.
6-Aminobenzopyrones, 5-iodo-6-aminobenzopyrones, Coumarins, isoquinolines, and quinizarines were claimed as antivirals in WO 92/18123; however, only 6-amino-benzopyrone and 5-iodo-6-aminobenzopyrone were tested. These compounds are postulated to inhibit adenosine diphosphoribosyl transferase thus stopping the retroviral reverse transcriptase.
Hei 3-227923 claimed coumarins with anti-HIV activity. However, only 4-hydroxycoumarin was specifically described without discussion of a mechanism of action.
World Patent 89/07939 claimed eight coumarin derivatives as HIV reverse transcriptase inhibitors with potential antiviral activity. These derivatives are hexachlorocoumarin, 7-acetoxycoumarin, and the structures shown below. ##STR2##
Warfarin (3-(.alpha.-acetonylbenzyl)4-hydroxycoumarin) shown below, was reported by R. Nagorny et al. in AIDS, 7: 129-130 (1993) as inhibiting cell-free and cell-mediated HIV infection. However, Warfarin was the only coumarin studied and its potential involvement in HIV inhibition was not specified. ##STR3##
Selected flavones, structurally different from the coumarins of the present invention, were reported by Fairli et al. (Biochem. Biophys. Res. Comm., 188: 631-637 (1992)) to be inhibitors of the HIV-1 protease. These compounds are shown below. ##STR4##